title: Impaired endocytosis in proximal tubule from subchronic exposure to cadmium involves angiotensin II type 1 and cubilin receptors.
abstract: BACKGROUND
  Chronic exposure to low cadmium (Cd) levels produces urinary excretion of low molecular weight proteins, which is considered the critical effect of Cd exposure. However, the mechanisms involved in Cd-induced proteinuria are not entirely clear. Therefore, the present study was designed to evaluate the possible role of megalin and cubilin (important endocytic receptors in proximal tubule cells) and angiotensin II type 1 (AT1) receptor on Cd-induced microalbuminuria.
  
  
  METHODS
  Four groups of female Wistar rats were studied. Control (CT) group, vehicle-treated rats; LOS group, rats treated with losartan (an AT1 antagonist) from weeks 5 to 8 (10 mg/kg/day by gavage); Cd group, rats subchronically exposed to Cd (3 mg/kg/day by gavage) during 8 weeks, and Cd + LOS group, rats treated with Cd for 8 weeks and LOS from weeks 5-8. Kidney Cd content, glomerular function (evaluated by creatinine clearance and plasma creatinine), kidney injury and tubular function (evaluated by Kim-1 expression, urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and glucose, and microalbuminuria), oxidative stress (measured by lipid peroxidation and NAD(P)H oxidase activity), mRNA levels of megalin, expressions of megalin and cubilin (by confocal microscopy) and AT1 receptor (by Western blot), were measured in the different experimental groups. Data were analyzed by one-way ANOVA or Kruskal-Wallis test using GraphPad Prism 5 software (Version 5.00). P < 0.05 was considered statistically significant.
  
  
  RESULTS
  Administration of Cd (Cd and Cd + LOS groups) increased renal Cd content. LOS-treatment decreased Cd-induced microalbuminuria without changes in: plasma creatinine, creatinine clearance, urinary NAG and glucose, oxidative stress, mRNA levels of megalin and cubilin, neither protein expression of megalin nor AT1 receptor, in the different experimental groups studied. However, Cd exposure did induce the expression of the tubular injury marker Kim-1 and decreased cubilin protein levels in proximal tubule cells whereas LOS-treatment restored cubilin levels and suppressed Kim-1 expression.
  
  
  CONCLUSIONS
  LOS treatment decreased microalbuminuria induced by Cd apparently through a cubilin receptor-dependent mechanism but independent of megalin.
authors.affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City, México. obarbier@cinvestav.mx.
authors.forename: Mitzi Paola
authors.initials: MP
authors.lastname: Santoyo-Sánchez
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
authors.forename: Eduardo
authors.initials: E
authors.lastname: Molina-Jijón
authors.forename: Laura
authors.initials: L
authors.lastname: Arreola-Mendoza
authors.forename: Rafael
authors.initials: R
authors.lastname: Rodríguez-Muñoz
authors.forename: Olivier Christophe
authors.initials: OC
authors.lastname: Barbier
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism*; D000818:Animals; D002105:Cadmium Poisoning / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D005260:Female; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000503:physiopathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor